JP2003531902A - Pyrimidinylmethylindole derivatives with antibacterial activity - Google Patents

Abstract

This invention relates to indole derivatives of the general formula (I) wherein R<1 >is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl or phenylalkyl; R<2 >is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl; R<3 >is hydrogen, alkyl; and R<4 >is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, heterocyclylalkyl, or phenylalkyl; and pharmaceutically acceptable acid addition salts of these compounds, there use as therapeutically active substances; medicaments based on these substances, optionally in combination with sulphonamides, and their production; the use of these substances as medicaments and for the production of antibacterially-active medicaments; as well as the manufacture of the compounds of formula (I) and their pharmaceutically acceptable acid addition salts and intermediates for their manufacture.

Description

Detailed Description of the Invention

[0001]   The present invention has the general formula (I):

[0002]

[Chemical 6]

[Wherein R ¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfur. Famoyl, heterocyclylalkyl or phenylalkyl; R ² is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl; R ³ is hydrogen, alkyl; and R ⁴ is alkyl, Alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-ar And a pharmaceutically acceptable acid addition salt of these compounds.

The above compounds are novel and have useful antibiotic activity. These can be used in the control and prevention of infectious diseases. In particular, these are Streptoc
It exhibits remarkable antibacterial activity, including multidrug-resistant Gram-positive strains such as occus pneumoniae and Staphylococcus aureus. These compounds can also be administered in combination with known antibacterial actives and can exhibit synergistic effects. Typical combination partners are, for example, sulfonamides, and these can be mixed with the compounds of formula (I) or salts thereof in various ratios.

The object of the present invention is to provide compounds of formula (I) and their pharmaceutically acceptable salts themselves, and their use as therapeutically active substances; these, optionally in combination with sulfonamides. Pharmaceuticals based on the substances and their manufacture; as pharmaceuticals,
And the use of these substances for the manufacture of antibacterial active pharmaceuticals; furthermore the preparation of compounds of formula (I) and their pharmaceutically acceptable salts, and intermediates for their preparation.

The groups specified above are defined below. For combined groups such as cycloalkylalkyl, etc., correspondingly typical examples will be understood.

The term “halogen” means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

The term “alkyl”, unless specified otherwise, means a straight or branched chain group having 6 or fewer, preferably 4 or fewer carbon atoms. Such groups are, for example, methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl or t-butyl.

“Alkenyl” and “alkynyl” are unsaturated straight or branched chains having 6 or less, preferably 4 or less carbon atoms, each having at least one double bond or at least one triple bond. Hydrocarbon groups such as vinyl, 2-propenyl, 1,3-butadienyl, isopropenyl, 1-propynyl, 2-propynyl,
1-butynyl and 3-butynyl are meant.

“Cycloalkyl” is a cyclic hydrocarbon group having from 3 to 6 carbon atoms, eg,
It means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

“Cycloalkylalkyl” means a combination of cycloalkyl and alkyl as defined above, eg cyclopropylmethyl, 2-cyclopropylethyl, cyclopentylmethyl.

“Alkanoyl” means a formyl group or an alkyl-CO— group, where “alkyl” is as defined above.

“Heterocyclyl” means a heterocyclic saturated 3 to 6 membered ring containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, for example aziridinyl, oxiranyl, thiylanyl, azetidinyl, Oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxolanyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, 1,4-pyrazolidinyl, pyrazolidinyl, pyrazolidinyl. Dioxo-8-aza
Refers to spiro [4.5] decan-8-yl and the like, which heterocyclic group may be substituted by one or more substituents such as alkyl, alkoxy, halogen, alkanoyl or phenyl.

“Phenyl” means unsubstituted phenyl and alkyl, alkoxy, halogen,
Refers to phenyl substituted with one or more substituents such as alkanoyl or phenyl.

Preferred compounds of formula (I) are those wherein R ¹ is alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl, especially isopropylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, cyclopropylsulfonyl or cyclopropylmethyl. A compound that is a sulfonyl. A preferred value for R ² is hydrogen or alkyl, especially methyl. A preferred value for R ³ is hydrogen or methyl. The preferred meaning of R ⁴ is alkyl, especially ethyl.

A preferred compound of formula (I) is cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5
-Ylmethyl) -1-ethyl-1H-indole-4-yl ester; 2-methyl-propane-1-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indole -4-yl ester; rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-1H-indol-4-yl ester; cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5
-Ylmethyl) -1-ethyl-3-methyl-1H-indol-4-yl ester; and rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-2-methyl-1H-indol-4-yl ester as well as the pharmaceutically acceptable acid addition salts of these compounds.

The compounds of formula (I) form pharmaceutically acceptable acid addition salts with organic and inorganic acids. Examples of acid addition salts of the compounds of formula (I) are mineral acids such as salts with hydrohalic acids (such as hydrochloric acid, hydrobromic acid and hydroiodic acid), sulfuric acid, nitric acid, phosphoric acid and the like, organic acids. Sulfonic acids, such as alkyl- and arylsulfonic acids (methanesulfonic acid,
p-toluenesulfonic acid, benzenesulfonic acid, etc.), and further organic carboxylic acids such as acetic acid, tartaric acid, maleic acid, citric acid, benzoic acid, salicylic acid,
It is a salt with ascorbic acid.

The compounds of formula (I) and their pharmaceutically acceptable salts can be prepared according to the invention as follows: i) general formula (II):

[0019]

[Chemical 7]

[Wherein R ^{1 to} R ⁴ have the same meanings as defined above and X represents a leaving group], and the compound represented by the formula (ii) is reacted with guanidine or a salt thereof. III):

[0021]

[Chemical 8]

Wherein R ³ is as defined above and R ^1A , R ^2A and R ^4A are as defined for R ¹ , R ² and R ⁴ , but at least one of them is hydrogen. Or at least one of the groups R ¹ , R ² and R ⁴ is introduced into the compound represented by the formula 1) or iii) the compound of the formula (I) is converted into a pharmaceutically acceptable salt.

Starting material (II) of process variant i) of the process according to the invention, wherein the ═CHX group is (E)
-Or (Z) configuration) may be cyclized with guanidine or a salt thereof, preferably in an inert organic solvent, preferably a lower alkanol, such as ethanol, or dimethylsulfoxide, tetrahydrofuran or It is carried out in dioxane at about 50-100 ° C. Guanidine is preferably used as a salt, eg as the hydrochloride salt, in which case the reaction is preferably carried out in the presence of a base, eg potassium t-butyrate. The leaving group X is preferably bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy,
Phenylsulfonyloxy or p-tolylsulfonyloxy.

Variant ii) of the method of the invention comprises several alternatives. R ² of the phenyl or heterocyclyl group has the general formula (IIIa):

[0025]

[Chemical 9]

[0026] The compound represented by the general formula (IV):

[0027]

[Chemical 10]

It can be introduced by reacting with a compound represented by [wherein R ¹ , R ³ and R ⁴ have the same meanings as described above, and R ²¹ is phenyl (which may be substituted). And one of the symbols: X and Y represents a leaving group, and the other is a group that is released with this leaving group].

In this reaction, the groups: X and Y can be: X = bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy; and Y = (OH) ₂ B-.

Boronic acid derivatives (also known as “Suzuki coupling”)
This reaction with IV) is preferably carried out in an inert organic solvent such as, for example, dioxane, tetrahydrofuran or dimethylsulfoxide, at a temperature between about 20 ° C. and the boiling point of the reaction mixture. Preferably, a base such as an alkali metal carbonate, for example potassium carbonate, is added with a catalyst, preferably a palladium complex such as tetrakistriphenylphosphine-palladium.

Y = —Sn (lower alkyl) ₃ , for example, —Sn (CH ₃ ) ₃ or —Sn (
n-butyl) ₃ (“Stille reaction”); —MgHal (“Grignard coupling”); or —ZnHal, and with Hal = chlorine, bromine or iodine (“Negishi coupling”). One compound (IV) has the formula (IV
) Can be used as a reaction partner in the above reaction. No base is used in this reaction, but preferably the catalysts described above are used. It is also advantageous to add an inert salt, especially lithium chloride.

Further the above reaction, exchanged substituents: X and Y, for _{example, X = -Sn (CH 3)} 3, a -MgHal or -ZnHal, and Y = bromine, iodine, methylsulfonyloxy, It can also be carried out with trifluoromethylsulfonyloxy, phenylsulfonyloxy, p-tolylsulfonyloxy. The reaction conditions are essentially the same.

Yet another method for introducing R ² is halogenation, alkanoylation, aminomethylation and conversion of aminomethyl group to methyl, all of steps (p), (r)
, (S) and (t) according to the methods disclosed below.

The groups R ¹ and R ⁴ are represented by the general formulas (IIIb) and (IIIc):

[0035]

[Chemical 11]

Can be introduced by reacting a compound represented by: with a compound represented by the general formula: R ¹ Z or R ⁴ Z (wherein R ^{1 to} R ⁴ have the same meanings as described above). , And Z is a leaving group).

In the case of an alkylation reaction, the leaving group Z is preferably bromine, iodine, methylsulfonyloxy, trifluoromethylsulfonyloxy, phenylsulfonyloxy or p-tolylsulfonyloxy. In the sulfonylation reaction, Z is preferably chlorine. The reaction is preferably carried out in a polar aprotic solvent such as N, N-dimethylformamide and in the presence of a base such as potassium tert-butoxide at a temperature of about -20 ° C to 20 ° C. .

The preparation of the pharmaceutically acceptable acid addition salts of the compounds of formula (I) of process variant iii) is carried out in a manner known per se, for example by reacting a compound of formula (I) with an organic or inorganic acid, This can be achieved by reacting in an organic solvent such as ethanol, methanol or acetone. The temperature at which salt formation occurs is not critical. This is generally room temperature, but can be lower or higher, for example in the range 0 ° C to + 50 ° C.

Various possibilities for synthesizing compounds of general formula (I) are outlined in the reaction schemes 1 to 6 below.

[0040]

[Chemical 12]

In Schemes 1-6, the symbols are defined as follows: R ¹ , R ² , R ³ and R ⁴ are as defined above; R ⁵ is alkyl, alkenyl, alkynyl, cycloalkyl , Cycloalkylalkyl, heterocyclylalkyl or phenylalkyl; R ⁶ represents a suitable protecting group, especially 2-trimethylsilanyl-ethoxymethyl; R ⁷ represents a suitable protecting group, especially 2-trimethylsilanyl- Represents ethoxymethyl, benzyl or a derivative thereof; R ⁸ represents alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclylalkyl or phenylalkyl; R ⁹ represents a suitable protecting group, especially tetrahydropyran-2-yl or a derivative thereof. the expressed; R ¹⁰ is a suitable protecting group, especially alkylsulfonyl, phenylsulfonyl, It represents a derivative thereof; R ¹¹ is aryl, heterocyclyl; R ¹² is hydrogen, alkyl; R ¹³ is a nitrogen-containing heterocyclic ring bonded through the nitrogen atom, especially morpholin -4
Dialkylamino, including -yl and thiomorpholin-4-yl.

Reaction steps (a)-(t) are preferably carried out as follows: (a) Alkylation of the hydroxyl of 1H-indole-4-ol. This reaction involves the reaction of a compound of the general formula: R ⁵ —X, where X is a leaving group, preferably Br, with a base in a polar aprotic solvent such as N, N-dimethylformamide. Preferably in the presence of potassium tert-butyrate at about 0-30 ° C.

(B) Reduction of the ester functional group of methyl 1H-indole-6-carboxylate to the corresponding alcohol. This reaction is carried out with an excess of aluminum hydride, especially diisobutylaluminum hydride, in a solvent such as tetrahydrofuran at about 0 to 0.
It is carried out at 20 ° C.

(C) Oxidation of the alcohol group of [1H-indol-6-yl] -methanol to the corresponding aldehyde. The reaction is carried out with excess manganese dioxide in a solvent such as dichloromethane at a temperature between 0 ° C. and the boiling point of the solvent.

(D) Protection of 1H-indole nitrogen. This reaction has the formula: R ⁶ -X (where X
Is a leaving group, for example Cl) and a base, preferably potassium te.
It is carried out in the presence of rt-butyrate in a polar solvent such as N, N-dimethylformamide at about 0-30 ° C.

(E) 1H-indole-6-carbaldehyde 5- (1H-indole-6
-Ylmethyl) -2,4-diaminopyrimidine conversion. The two consecutive steps are carried out by applying the method described in patent DE 2443682, (e1) base catalyzed condensation of 1H-indole-6-carbaldehyde with 3-anilinopropionitrile, and (e2)
It is carried out by subsequent treatment of the 1-anilino-2- (1H-indol-6-ylmethyl) acrylonitrile produced with guanidine.

(F) Cleavage of the 1H-indole nitrogen protecting group R ⁶ . The reaction is preferably carried out in tetrahydrofuran in the presence of tetrabutylammonium fluoride in the presence of ethylenediamine and a molecular sieve at a temperature between 20 ° C. and the boiling point of the solvent.

(G) Functionalization of 1H-indole nitrogen. This reaction has the formula: with a compound of R ⁸ -X (if the alkylation reaction) or R ¹⁴ -Cl (the case of sulfonation reaction), N, N
Carried out in a polar aprotic solvent such as dimethylformamide and in the presence of a base such as potassium tert-butoxide, at a temperature between -20 ° C and 20 ° C. X is a leaving group, preferably Br, and R ¹⁴ is alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, or N-cycloalkyl-N-alkylsulfamoyl.

(H) Functionalization of the 1H indole nitrogen. This reaction is carried out at −20 ° C. and 20 ° C. with a compound of formula R ⁸ —X in a polar aprotic solvent such as N, N-dimethylformamide and in the presence of a base such as potassium tert-butoxide. It is carried out at a temperature between ° C. X is a leaving group, preferably Br.

(I) Cleavage of the phenol protecting group R ⁷ . The reaction is carried out as follows: (i1) In the case of R ⁷ = 2-trimethylsilanyl-ethoxymethyl, by tetrabutylammonium fluoride in tetrahydrofuran or like sulfuric acid in lower alcohols. With any strong acid at temperatures between 0 ° C. and the boiling point of the solvent; (i2) in the case of R ⁷ = benzyl, lower alcohols or lower alkanecarboxylic acids by catalytic hydrogenation with hydrogen and palladium on activated carbon. About 0 in acid
It is carried out at 50 ° C., preferably room temperature.

(J) Functionalization of the hydroxyl of 1H-indole-4-ol. This reaction is carried out by reacting a compound of the formula: R ⁸ -X (for alkylation reactions) or R ¹⁴ -Cl (for sulfonation reactions) with a polar aprotic solvent such as N, N-dimethylformamide. And in the presence of a base such as potassium tert-butoxide at -20 ° C.
And at a temperature between 20 ° C. X is a leaving group, preferably Br, and R ¹⁴ is as defined above.

(K) Protection of the hydroxyl of 1H-indol-6-ylmethanol. The reaction is carried out with 3,4-dihydro-2H-pyran and a catalytic amount of pyridinium toluene-4-sulfonate in a solvent such as dichloromethane at about room temperature.

(L) Nitrogen protection of 1H-indole. This reaction is a suitable sulfonyl chloride R ¹⁰ -Cl, preferably a benzenesulfonyl chloride, about 0 to 50 ° C.
In a two-phase mixture of an aqueous alkali hydroxide solution and dichloromethane in the presence of a phase transfer catalyst such as tetrabutylammonium hydrogensulfate.

(M) Alkylation of C (2) of N (1) -protected 1H-indole. This reaction is
Deprotection with tert-butyllithium in a solvent such as tetrahydrofuran,
And subsequent treatment of the resulting 2-lithioindole with a compound of the formula: R ³ —X, where X is a leaving group, eg I.

(N) Cleavage of the hydroxyl protecting group R ⁹ . The reaction is carried out in a lower alcohol such as ethanol with a catalytic amount of pyridinium toluene-4-sulfonate at a temperature between about 30 ° C. and the boiling point of the solvent.

(O) Cleavage of the nitrogen protecting group R ¹⁰ of 1H-indole. This reaction is carried out by hydrolysis in aqueous base at a temperature between 20 ° C. and the boiling point of the solvent (wherein a lower alcohol and / or a water-miscible organic solvent such as tetrahydrofuran in order to increase the solubility). Add).

(P) Bromination of C (3) of 1H-indole. This reaction is preferably carried out with elemental bromine in a solvent such as N, N-dimethylformamide at about 0-40 ° C.
Done in.

(Q) Coupling reaction of 3-bromo-1H-indole with boronic acid: R ¹¹ -B (OH) ₂ (Suzuki coupling). The reaction is preferably carried out in an inert solvent such as 1,2-dimethoxyethane at a temperature between about 20 ° C. and the boiling point of the solvent. This reaction also requires a base, preferably an alkali carbonate such as potassium carbonate, and a catalytic amount of a palladium complex such as tetrakis (triphenylphosphine) palladium (0).

(R) Alkanoylation of C (3) of 1H-indole. This reaction is preferably carried out by the Vilsmeier method using N, N-disubstituted alkane amides such as N, N-dimethylformamide and phosphorus oxychloride as reagents,
And using the same N, N-dialkylalkanamide as a solvent at about 0 to 80 ° C.
Performed at the temperature of.

(S) Aminomethylation of C (3) of 1H-indole. This reaction is carried out by the Mannich method using a tertiary amine such as morpholine and formaldehyde as a reagent in a mixture of water and a lower alkanecarboxylic acid such as acetic acid at about 0 to 80 ° C. Done in.

(T) Conversion of 3- (aminomethyl) -1H-indole to 3-methyl-1H-indole. The reaction is carried out by catalytic hydrogenation using hydrogen and palladium on activated carbon in a lower alcohol at about 0-50 ° C., preferably at room temperature.

As mentioned above, the compounds of formula (I) and their pharmaceutically acceptable salts possess valuable antibacterial properties. They are active against a number of pathogenic microorganisms such as, for example, Staphylococcus aureus, Streptococcus pneumoniae due to their action of inhibiting bacterial dihydrofolate reductase (DHFR).

The inhibition of this enzyme was adopted as a measure for antibacterial activity. This is Bacc
Determined using the method of anari and Joyner (Biochemistry 20, 1710 (1981)); P
See also .G. Hartman et al., FEB 242, 157-160 (1988).

IC ₅₀ values (concentration at which the enzyme is inhibited by 50%) are determined graphically.

Tables 1 and 2 below contain the inhibitory concentrations determined in the above test for representative members of the compounds defined by formula (I). The following microorganisms were tested: Column 1: MIC Spn ATCC 49619; μg / ml (Steptococcus pne
umoniae ATCC 49619, trimethoprim- and penicillin-sensitive, reference strain, obtained from American Type Culture Collection). Column 2: MIC Spn 1/1; μg / ml (Steptococcus pneumoniae 1/1
, Trimethoprim- and penicillin resistance, serotype 6; clinical isolate, stored at -80 ° C). Reference: H. Locher et al., Can. J. Infect. Dis. 6: Suppl. C, p 469C. Column 3: DHFR Spn1 / 1; μM-IC ₅₀ value (μM) for the purified DHFR of the above strain Spn1 / 1 of Steptococcus pneumoniae.

[0066]

[Table 1]

The products of the invention can be used as medicaments, eg in the form of pharmaceutical preparations for enteral or parenteral administration. The products according to the invention are, for example, orally, for example, in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, for example in suppositories. It can be administered in a dosage form or parenterally, for example in the form of an injection solution. Therefore, the present invention also includes the formula (I
) Or a pharmaceutically acceptable acid addition salt thereof, alone or in combination with a sulfonamide, to a method for prophylactic and / or therapeutic treatment of infectious diseases.

The manufacture of the present pharmaceutical preparations is carried out in a manner familiar to the person skilled in the art, by combining the substances according to the invention with other therapeutically useful substances, if desired, in a suitable, non-toxic, inert treatment. This can be accomplished by formulating a dosage form with a compatible solid or liquid carrier material and, if desired, conventional formulation auxiliaries.

Not only inorganic carrier materials, but also organic carrier materials are suitable as such carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (but depending on the nature of the active substance, soft gelatine capsules do not require a carrier). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose. Suitable carrier materials for injectable solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

Conventional preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, flavoring agents, salts for changing the osmotic pressure, buffers, coating agents and antioxidants are considered as formulation auxiliaries. It

For parenteral administration, the compounds of formula (I) and salts thereof, respectively, are preferably lyophilized or dried, for dilution with conventional carriers such as water or isotonic saline. Supplied as a powder.

As already mentioned, the compounds of formula (I) and their salts have antibacterial activity. They inhibit bacterial dihydrofolate reductase and are compatible with sulfonamides (eg sulfisoxazole, sulfadimethoxine, sulfamethoxazole, 4-sulfanilamide-5,6-dimethoxy-pyrimidine, 2-sulfanyl). Amido-4,5-dimethyl-pyrimidine or sulfaquinoxaline, sulfadiazine, sulfamonomethoxine, 2-sulfanilamide-4,5-dimethyl-isoxazole, etc.) and other inhibitors of enzymes involved in folic acid biosynthesis (such as (Eg, pteridine derivatives) to enhance the antibacterial activity.

The treatment of the host, in particular the warm-blooded host, with a compound of formula (I) or a sulfonamides thereof is considered for example oral, rectal and parenteral administration in human medicine. It For adults, a daily dose of about 0.2 g to about 2 g of the compound of formula (I) of the invention is contemplated. When administered in combination with antibacterial sulfonamides, the ratio of compound (I) to sulfonamide can be varied within wide limits; for example 1:40 (parts by weight) and 1: 1 (parts by weight). Between 1:10 and 1: 1 is a preferred ratio. Thus, for example, one tablet contains 80 mg of compound (I
) And 400 mg of sulfamethoxazole, and one pediatric tablet can contain 20 mg of compound (I) of the present invention and 100 mg of sulfamethoxazole; syrup (5 ml) Per hit may contain 40 mg of compound (I) and 200 mg of sulfamethoxazole.

The compounds of formula (I) are each characterized by a high antibacterial activity, as well as a pronounced synergistic effect in combination with a sulfonamide and a good tolerability.

[0075]   The invention is illustrated by the following examples.

Example 1 (Key Intermediate) 5- (4-Ethoxy-1H-indol-6-ylmethyl) -pyrimidine-2,
4-diamine. This compound was prepared from 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (DE 2508251) via steps a) -f) as described below.

A) 4-Ethoxy-1H-indole-6-carboxylic acid methyl ester. Potassium tert-butyrate (581 mg, 5.18 mmol) was added to N, N at 0 ° C.
4-Hydroxy-1H-indole-6 in dimethylformamide (10 mL)
-Carboxylic acid methyl ester (900 mg, 4.71 mmol) and iodoethane (0.
81 g, 5.18 mmol) was added. The reaction mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 90 minutes, then poured onto ice and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. Column chromatography (SiO ₂ ; n-hexane / ethyl acetate, 3: 1) gave the title compound (275 m
g, 22%). Yellow solid. MS (EI): 219.1 (M ⁺ ).

B) (4-Ethoxy-1H-indol-6-yl) -methanol. Diisobutylaluminium hydride (1M solution in tetrahydrofuran, 4.9 mL
4.9 mmol) at 0 <0> C over 20 min. In tetrahydrofuran (10 mL).
Ethoxy-1H-indole-6-carboxylic acid methyl ester (270 mg, 1.
23 mmol). After 2.5 hours, the reaction was quenched by the addition of water (2 mL). Brine (10 mL), saturated aqueous ammonium chloride solution (10 mL), ethyl acetate (20 mL) were added, the mixture was filtered through a filter aid, the organic layer was separated, dried (MgSO ₄ ) and the solvent was distilled off. The title compound (218 mg, 89%) was obtained.
Light brown solid. MS (EI): 191 (M ⁺ )

C) 4-Ethoxy-1H-indole-6-carbaldehyde. (4-Ethoxy-1H-indol-6-yl) -methanol (180 mg, 0
． A mixture of 941 mmol) and manganese dioxide (410 mg, 4.71 mmol) was refluxed in dichloromethane (10 mL) for 16 hours. After filtration with a filter aid and evaporation of the solvent, the title compound (147 mg, 78%) was obtained. Dark brown solid. MS (EI): 189 (M ⁺ )

D) 4-Ethoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-
Indole-6-carbaldehyde. Potassium tert-butyrate (753 mg, 6.71 mmol) was added to N, N at 0 ° C.
4-ethoxy-1H-indole-6- in dimethylformamide (25 mL)
Carbaldehyde (1.27 g, 6.71 mmol) was added to the solution. After 1 hour 2- (trimethylsilyl) ethoxymethyl chloride (1.23 g, 7.38 mmol) was added, then after 2 hours the mixture was potassium tert-butyrate (377 mg, 3.3).
6 mmol) and 2- (trimethylsilyl) ethoxymethyl chloride (616 mg, 3.6
9 mmol). Allow the reaction mixture to warm to room temperature, stir overnight, then pour onto ice and extract with ethyl acetate. The organic layer was washed with brine and dried (MgSO ₄
Then, the solvent was distilled off. Flash chromatography (SiO ₂ ; n-hexane / ethyl acetate, 2: 1) gave the title compound (2.14 g, 100%). Yellow oil. MS (EI): 319 (M ⁺ )

E) 5- [4-ethoxy-1- (2-trimethylsilanyl-ethoxymethyl)-
1H-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. Potassium tert-butyrate (90 mL) in tert-butanol (7.5 mL).
A hot solution of 0 mg, 8.02 mmol) at room temperature in 4 mL of methyl sulfoxide (25 mL).
Of -ethoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-indole-6-carbaldehyde (2.14 g, 6.69 mmol) and 3-anilinopropionitrile (1.08 g, 7.36 mmol) Added to the solution. After 90 minutes, this solution was treated with water and the resulting suspension was stirred for 2 hours. The precipitate was collected by filtration and dried. This material was treated with guanidine hydrochloride (1.9 mL) in ethanol (100 mL).
0 g, 19.9 mmol) and potassium tert-butyrate (2.23 g, 19.9).
mmol) and the reaction mixture was refluxed for 16 hours, then most of the solvent was evaporated and ether (50 mL) was added. Insoluble material was removed by filtration, the filtrate was washed with water, dried (MgSO ₄₎ and the solvent was evaporated. The residue was washed with diethyl ether / n-hexane, 4: 3 (70 mL) to give the title compound (1
． 71 g, 62%) was obtained. Light brown solid. MS (ISP): 414.4 ([M + H] ⁺ ).

F) 5- (4-ethoxy-1H-indol-6-ylmethyl) -pyrimidine-
2,4-diamine. 5- [4-ethoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1
H-indol-6-ylmethyl] -pyrimidine-2,4-diamine (1.20
g, 2.90 mmol), ethylenediamine (785 mg, 13.1 mmol) and tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 8.7 mL, 8.7).
solution) was stirred at 80 ° C. for 18 hours in the presence of molecular sieve (4Å). After separation of this sieve, the reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. Flash chromatography (SiO ₂ ; CH ₂ Cl ₂ / MeOH / NH ₄ OH, 90: 10: 1)
Gave the title compound (610 mg, 74%). Yellow solid. MS (ISP): 284.2 ([M + H] ⁺ ).

Example 2a 5- (1-Cyclopropylmethyl-4-ethoxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. Potassium tert-butyrate (67 mg, 0.60 mmol) at room temperature in N, N-
5- (4-ethoxy-1H-indole-6 in dimethylformamide (2 mL)
-Ylmethyl) -pyrimidine-2,4-diamine (Example 1; 141 mg, 0.5
0 mmol) solution. After 30 minutes, (bromomethyl) cyclopropane (87 mg
, 0.65 mmol) and then after 1 hour the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer dried (MgSO ₄₎ and evaporated. Column chromatography (SiO ₂ ; CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1:
0.05) gave the title compound (65 mg, 38%). Off-white solid. MS (ISP): 338.3 ([M + H] ⁺ ).

Example 2b 5- (1-Cyclopentyl-4-ethoxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 5- (4-ethoxy-1H-indol-6-ylmethyl)-
Prepared by reaction of pyrimidine-2,4-diamine (Example 1; 100 mg, 0.353 mmol) with bromocyclopentane (334 mg, 2.24 mmol) according to the procedure detailed in Example 2a. Yield: 66 mg (53%). Off-white solid. MS (ISP): 352.3 ([M + H] ⁺ ).

Example 2c 5- (1-Benzyl-4-ethoxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 5- (4-ethoxy-1H-indol-6-ylmethyl)-
Prepared according to the procedure detailed in Example 2a by reaction of pyrimidine-2,4-diamine (Example 1; 100 mg, 0.353 mmol) with benzyl bromide (73 mg, 0.42 mmol). Yield: 100 mg (76%). Off-white solid. MS (ISP): 374.4 ([M + H] ⁺ ).

Example 2d 5- [4-Ethoxy-1- (propane-2-sulfonyl) -1H-indole-
6-ylmethyl] -pyrimidine-2,4-diamine. Potassium tert-butyrate (71 mg, 0.64 mmol) at room temperature in 5- (4-ethoxy-1H-indol-6-ylmethyl)-in N, N-dimethylformamide (4 mL) containing molecular sieves (4Å). Pyrimidine-2,4-diamine (
Example 1; 150 mg, 0.53 mmol) was added to the solution. Propane-2 after 20 minutes
-Sulfonyl chloride (91 mg, 0.64 mmol) was added, then after 90 min the reaction mixture was treated with potassium tert-butyrate (24 mg, 0.21 mmol) and propane-2-sulfonyl chloride (31 mg, 0.21 mmol). After 90 minutes, the reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was dried (MgSO _4), and evaporated. Flash chromatography (SiO ₂ ; CH ₂ Cl ₂ /
MeOH / NH ₄ OH, 19: 1: 0.05) gave the title compound (109 mg, 5
3%) was obtained. White solid. MS (EI): 389 (M ⁺ ).

Example 2e 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -4-ethoxy-indole-1-sulfonic acid dimethylamide. Potassium tert-butyrate (42 mg, 0.37 mmol) was added to 5- (4-ethoxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine (Example) in N, N-dimethylformamide (5 mL). 1; 100 mg, 0.353 mm
ol) solution. After 15 minutes, dimethylsulfamoyl chloride (53 mg, 0
． (37 mmol) was added, then after 30 minutes the solvent was evaporated and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried (M
gSO ₄ ) and the solvent was distilled off. The residue was suspended in ether and the precipitate was collected to give the title compound (73 mg, 53%). Off-white solid.
MS (ISP): 374.4 ([M + H] ⁺ ).

Example 3 5- (4-Ethoxy-1-ethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound was prepared from 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (DE 2508251) via steps a) -d) as described below.

A) 4-Ethoxy-1-ethyl-1H-indole-6-carboxylic acid methyl ester. Potassium tert-butyrate (3.13 g, 27.9 mmol) over 30 minutes, 4-hydroxy-1H-indole-6-carboxylic acid methyl ester (4.8.
To a solution of 5 g, 25.4 mmol) and bromoethane (3.04 g, 27.9 mmol) was added at 0 ° C. After 75 minutes, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried (MgSO _4), and evaporated. By column chromatography (SiO ₂ ; hexane / ethyl acetate, 3: 1), the title compound (550 mg,
9%) was obtained. Light yellow solid. MS (EI): 247 (M ⁺ )

B) (4-Ethoxy-1-ethyl-1H-indol-6-yl) -methanol. This compound comprises 4-ethoxy-1-ethyl-1H-indole-6-carboxylic acid methyl ester (540 mg, 2.18 mmol) and diisobutylaluminium hydride (1M solution in tetrahydrofuran, 6.5 mL, 6.5 mmol). Depending on the reaction
Prepared according to the procedure detailed in Example 1, Step b. Yield: 457 mg (95
%). Light yellow solid. MS (EI): 219 (M ⁺ )

C) 4-Ethoxy-1-ethyl-1H-indole-6-carbaldehyde. This compound is (4-ethoxy-1-ethyl-1H-indol-6-yl)
-Methanol (431 mg, 1.97 mmol) and manganese dioxide (1.03 g, 11
． 7 mmol) and prepared according to the procedure detailed in Example 1, step c. Yield: 364 mg (85%). Light yellow solid. MS (EI): 217 (M ⁺ )

D) 5- (4-Ethoxy-1-ethyl-1H-indol-6-ylmethyl)-
Pyrimidine-2,4-diamine. This compound was prepared from 4-ethoxy-1-ethyl-1H-indole-6-carbaldehyde (316 mg, 1.46 mmol), 3-anilinopropionitrile (234 mg).
, 1.60 mmol) and guanidine hydrochloride (256 mg, 2.67 mmol) according to the procedure detailed in Example 1, step f. Yield: 165 mg (36%)
. Light brown solid. MS (ISP): 312.2 ([M + H] ⁺ ).

Example 4 (Key Intermediate) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-methyl-1H-
Indole-4-ol. This compound is obtained from 4-acetyl-1H-indole-6-carboxylic acid methyl ester (J. Prakt. Chem. 1973, 315, 295-299) via steps a) to g) as described below. Manufactured.

A) 1-Acetyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H
-Indole-6-carboxylic acid methyl ester. Potassium tert-butyrate (477 mg, 4.17 mmol) was added to a solution of 4-acetyl-1H-indole-6-carboxylic acid methyl ester (972 mg, 4.17 mmol) in N, N-dimethylformamide (15 mL) at 0 ° C. Added in. After 1 hour 2- (trimethylsilyl) ethoxymethyl chloride (849 mg, 4.58 mmol)
Was added, then after 2 hours, the reaction mixture was poured onto ice and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO ₄₎ and evaporated to give the title compound (1.40g, 92%). Light brown solid. MS (ISP): 364.4 ([M + H] ^+), 381.4 ([M + NH _4] ⁺⁾

B) 4- (2-Trimethylsilanyl-ethoxymethoxy) -1H-indole-
6-carboxylic acid methyl ester. 1-Acetyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carboxylic acid methyl ester (4 in methanol (200 mL), water (50 mL), and saturated aqueous sodium hydrogen carbonate solution (50 mL). .50 g, 12.
4 mmol) suspension was stirred at room temperature for 105 minutes, then poured onto ice and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give the title compound (3.52g, 91%). Brown oil. MS (EI): 263 _{([M-CH 2 O-C 2} H 4 ] ^+), 321 (M ⁺⁾

C) 1-Methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-
Indole-6-carboxylic acid methyl ester. Potassium tert-butyrate (2.98 g, 26.0 mmol) was added to 4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carboxylic acid methyl ester (N, N-dimethylformamide (110 mL) in methyl ester ( 7.60 g,
23.6 mmol). After 45 minutes iodomethane (3.73 g, 26.0
mmol) and then 45 minutes later, the reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water and brine, dried (MgSO ₄ ) and evaporated to remove the title compound (
7.92 g, 100%) was obtained. Red oil. MS (EI): 277 _{([M-CH 2 O-C 2} H 4 ] ^+), 335 (M ⁺⁾

D) [1-Methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H
-Indol-6-yl] -methanol. This compound was prepared by dissolving 1-methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carboxylic acid methyl ester (7.98 g, 23.
8 mmol) and diisobutylaluminum hydride (1M solution in tetrahydrofuran,
96 mL, 96 mmol), prepared according to the procedure detailed in Example 1, step b. Yield: 6.32 g (86%). Red oil. MS (ISP): 308.3 ([M + H] ⁺ ).

E) 1-Methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-
Indole-6-carbaldehyde. This compound was prepared as follows: [1-Methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indol-6-yl] -methanol (6.27 g, 20.4 mm)
ol) with manganese dioxide (9.85 g, 102 mmol) to give Example 1,
Prepared according to the procedure detailed in step c. Yield: 6.06 g (97%). Yellow solid. MS (EI): 247 _{([M-CH 2 O-C 2} H 4 ] ^+), 305 (M ⁺⁾

F) 5- [1-methyl-4- (2-trimethylsilanyl-ethoxymethoxy)-
1H-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. Potassium tert-butyrate (2.6 mL) in tert-butanol (20 mL).
A hot solution of 8 g, 23.4 mmol) was added to 1-methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole- in methylsulfoxide (70 mL).
Added to a room temperature solution of 6-carbaldehyde (5.95 g, 19.5 mmol) and 3-anilinopropionitrile (3.20 g, 21.4 mmol). After 2 hours, the solution was diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄₎ and the solvent was evaporated. Dissolve this material in ethanol (70 mL) and add ethanol (210
guanidine hydrochloride (6.21 g, 64.4 mmol) in (mL) and the mixture was stirred at 70 ° C. for 22 hours. Most of the solvent was distilled off and the residue was partitioned between water and ether. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. Flash chromatography (SiO ₂ ; CH ₂ Cl ₂ / MeOH / N
H ₄ OH, 19: 1: 0.05) gave the title compound (3.32 g, 43%). Yellow solid. MS (ISP): 400.4 ([M + H] ⁺ ).

G) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-methyl-1
H-indole-4-ol. A solution of sulfuric acid (7.25 mL) in methanol (240 mL) was added at room temperature over 30 minutes to 5- [1- (1-) in methanol (240 mL) and tetrahydrofuran (240 mL).
Methyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indol-6-ylmethyl] -pyrimidine-2,4-diamine (3.22 g, 8.05)
mmol) solution. After 20 minutes the product was precipitated by addition of NH ₄ OH (36 mL). The solvent was evaporated, the residue was suspended in water (160 mL), the pH was adjusted to 9-10 with 25% aqueous ammonia and the mixture was stirred for 45 minutes. The precipitate was filtered, washed with water and dried to give the title compound (2.17g, 10
0%). Yellow solid. MS (ISP): 270.4 ([M + H] ⁺ )

Example 5a 5- (4-Cyclopropylmethoxy-1-methyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. Potassium tert-butyrate (82 mg, 0.72 mmol) at 0 ° C. in N, N-
6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-methyl-1H-indol-4-ol (Example 4;) in dimethylformamide (16.5 mL).
162 mg, 0.60 mmol). After 45 minutes, this solution was treated with (bromomethyl) cyclopropane (100 mg, 0.72 mmol). The reaction mixture was allowed to warm to room temperature, stirred for 2.5 hours, then poured into ice water, adjusted to pH 9-10 with 25% aqueous ammonia solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO ₄₎ and the solvent was evaporated. Column chromatography (SiO ₂ ; CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.05) gave the title compound (127 mg, 65%). Yellow solid. MS (ISP): 324.4 ([M + H] ⁺ ).

Example 5b 5- (4-isopropoxy-1-methyl-1H-indol-6-ylmethyl)
-Pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Methyl-1H-indole-4-ol (Example 4; 293 mg, 1.09 mmol)
) With 2-bromopropane (162 mg, 1.31 mmol) to give Example 5
Prepared according to the procedure detailed in a. Yield: 132 mg (39%). Light orange solid. MS (ISP): 312.2 ([M + H] ⁺ ).

Example 5c Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-methyl-1H-indol-4-yl ester. Potassium tert-butyrate (150 mg, 1.31 mmol) at 0 ° C. (ice bath) in 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-methyl in N, N-dimethylformamide (33 mL). -1H-Indol-4-ol (Example 4; 293 mg, 1.09 mmol) was added to the solution. After 30 minutes, the solution was propane-
Treatment with 2-sulfonyl chloride (190 mg, 1.31 mmol) and removal of ice bath. After 2.5 hours, the reaction mixture was poured into ice water, adjusted to pH 9-10 with 25% aqueous ammonia solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO ₄₎ and the solvent was evaporated. Column chromatography (
SiO ₂ ; CH ₂ Cl ₂ / MeOH / NH ₄ OH, 19: 1: 0.05) gave the title compound (153 mg, 37%). White solid. MS (ISP): 376.4 ([M + H] ⁺ ).

Example 5d 2-Methyl-propane-1-sulfonic acid 6- (2,4-diamino-pyrimidine-
5-ylmethyl) -1-methyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Methyl-1H-indole-4-ol (Example 4, 269 mg, 1.00 mmol
) And 2-methylpropane-1-sulfonyl chloride (188 mg, 1.20 mmol)
Was prepared according to the procedure detailed in Example 5c. Yield: 58
mg (15%). White solid. MS (ISP): 390.3 ([M + H] ⁺ ).

Example 5e rac-Butane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-methyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Methyl-1H-indole-4-ol (Example 4; 294 mg, 1.09 mmol)
) With rac-butane-2-sulfonyl chloride (205 mg, 1.31 mmol) prepared according to the procedure detailed in Example 5c. Yield: 107mg
(25%). White solid. MS (ISP): 390.3 ([M + H] ⁺ ).

Example 6 (Key Intermediate) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-
Indole-4-ol. This compound is 4- (2-trimethylsilanyl-ethoxymethoxy) -1H-
Prepared from indole-6-carboxylic acid methyl ester (Example 4, step b) via steps a) -e) as described below.

A) 1-Ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-
Indole-6-carboxylic acid methyl ester. Potassium tert-butyrate (3.92 g, 34.2 mmol) at room temperature, 4-
(2-Trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carboxylic acid methyl ester (10.0 g, 31.1 mmol) was added to the solution. After 45 minutes, the solution was treated with bromoethane (3.77 g, 34.2 mmol), then 45
After minutes, the solvent was distilled off, and the residue was partitioned between ethyl acetate and saturated aqueous ammonium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, and brine, dried (MgSO ₄ ) and the solvent was evaporated to give the title compound (10.1 g,
93%). Red solid. MS (ISP): 350.3 ([M + H] ⁺ ).

B) [1-Ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H
-Indol-6-yl] -methanol. This compound was prepared from 1-ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carboxylic acid methyl ester (9.09 g, 2.6).
0 mmol) and diisobutylaluminium hydride (1M solution in tetrahydrofuran,
104 mL, 104 mmol) and prepared according to the procedure detailed in Example 1, step b. Yield: 7.86 g (94%). Orange oil. MS (EI): 263 _{([M-CH 2 O-C 2} H 4 ] ^+), 321 (M ⁺⁾

C) 1-Ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-
Indole-6-carbaldehyde. This compound was prepared as [1-ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indol-6-yl] -methanol (7.72 g, 2.40 mm).
ol) with manganese dioxide (11.6 g, 120 mmol) to give Example 1,
Prepared according to the procedure detailed in step c. Yield: 7.49 g (98%). Yellow solid. MS (EI): 261 _{([M-CH 2 O-C 2} H 4 ] ^+), 319 (M ⁺⁾

D) 5- [1-Ethyl-4- (2-trimethylsilanyl-ethoxymethoxy)-
1H-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound was prepared from 1-ethyl-4- (2-trimethylsilanyl-ethoxymethoxy) -1H-indole-6-carbaldehyde (630 mg, 1.97 mmol), 2
Prepared from anilinopropionitrile (324 mg, 2.17 mmol) and guanidine hydrochloride (634 mg, 6.60 mmol) according to the procedure detailed in Example 4, step f. Yield: 425 mg (53%). Yellow solid. MS (ISP): 414.4 ([M + H] ⁺ ).

E) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-1
H-indole-4-ol. Tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 33.4
mL, 33.4 mmol) and ethylenediamine (3.02 g, 50.1 mmol) at room temperature containing 5- (1-ethyl-4- (5) in N, N-dimethylformamide (50 mL) containing molecular sieves (4Å). 2-trimethylsilanyl-ethoxymethoxy) -1H
-Indol-6-ylmethyl] -pyrimidine-2,4-diamine (4.60 g
(11.1 mmol). After heating this mixture at 80 ° C. for 3.5 hours, the solvent was distilled off. The residue was dissolved in hot methanol (500 mL) and SiO ₂ (10 g)
Was added, the solvent was evaporated, the residue was added to a column (90 g, SiO ₂ ) and chromatographed (CH ₂ Cl ₂ / MeOH / NH ₄ OH, 90: 10: 1) to give the crude product. Was obtained, which was suspended in ether. The precipitate was filtered to give the title compound (1.04 g, 33%). Yellow solid. MS (ISP): 284.2 ([M + H] ⁺ ).

Example 7a 5- (4-Cyclopropylmethoxy-1-ethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 94 mg, 0.33 mmol)
By the reaction of (bromomethyl) cyclopropane (55 mg, 0.40 mmol) with
Prepared according to the procedure detailed in Example 5a. Yield: 50 mg (45%). Yellow solid. MS (EI): 337 (M ⁺ ).

Example 7b 5- (1-Ethyl-4-methoxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.69 mmol)
) With iodomethane (118 mg, 0.83 mmol) and prepared according to the procedure detailed in Example 5a. Yield: 77 mg (37%). Orange solid. MS (ISP): 298.3 ([M + H] ⁺ ).

Example 7c 5- (1-Ethyl-4-isopropoxy-1H-indol-6-ylmethyl)
-Pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 292 mg, 1.03 mmol
) With 2-bromopropane (153 mg, 1.23 mmol) to give Example 5
Prepared according to the procedure detailed in a. Yield: 89 mg (27%). Yellow solid. MS (ISP): 326.4 ([M + H] ⁺ ).

Example 7d 5- (1-Ethyl-4-prop-2-ynyloxy-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 141 mg, 0.498 mm
ol) with propargyl chloride (70% solution in toluene, 66 μL, 0.60 mmol) prepared according to the procedure detailed in Example 5a. Yield: 48mg
(30%). Brown solid. MS (ISP): 322.3 ([M + H] ⁺ ).

Example 7e 5- [4-([1,3] dioxolan-2-ylmethoxy) -1-ethyl-1H
-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 57 mg, 0.20 mmol)
Prepared by reaction of 2-bromomethyl-1,3-dioxolane (40 mg, 0.24 mmol) with the procedure detailed in Example 5a. Yield: 21 mg (28
%). Yellow solid. MS (ISP): 370.3 ([M + H] ⁺ ).

Example 7f 5- (4-Cyclobutylmethoxy-1-ethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.69 mmol)
) With (bromomethyl) cyclobutane (128 mg, 0.83 mmol) prepared according to the procedure detailed in Example 5a. Yield: 69 mg (28%).
Orange solid. MS (ISP): 352.3 ([M + H] ⁺ ).

Example 7g 5- (1-Ethyl-4-isobutoxy-1H-indol-6-ylmethyl)-
Pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.69 mmol)
) With 1-bromo-2-methylpropane (118 mg, 0.83 mmol) prepared according to the procedure detailed in Example 5a. Yield: 71 mg (30%)
. Yellow solid. MS (EI): 339.2 (M ⁺ ).

Example 7h 5- [1-Ethyl-4- (1-methyl-cyclopropylmethoxy) -1H-indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.69 mmol)
) And 1-bromomethyl-1-methylcyclopropane (124 mg, 0.83 mmol)
Was prepared according to the procedure detailed in Example 5a. Yield: 16
7 mg (68%). Yellow solid. MS (ISP): 352.4 ([M + H] ⁺ ).

Example 7i rac-5- [1-ethyl-4- (tetrahydro-furan-2-ylmethoxy)
-1H-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 198 mg, 0.70 mmol)
) With rac-tetrahydrofurfuryl bromide (193 mg, 1.05 mmol) prepared according to the procedure detailed in Example 5a. Yield: 65 mg (25
%). Light brown solid. MS (ISP): 368.3 ([M + H] ⁺ ).

Example 8a Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester. Propane-2-sulfonyl chloride (180 mg, 1.24 mmol) and potassium tert-butyrate (142 mg, 1.24 mmol) at room temperature in 6- (2,4-diamino-pyrimidine in N, N-dimethylformamide (30 mL). -5-ylmethyl) -1-ethyl-1H-indole-4-ol (293 mg, 1.03 mmol
) Solution. After 20 minutes, the reaction mixture was poured into ice water and the pH was adjusted to 9-10 with 25% aqueous ammonia solution. The mixture was stirred for 5 minutes and extracted with ethyl acetate. The organic layer was washed with water and brine, dried (MgSO ₄₎ and the solvent was evaporated. Flash chromatography (SiO ₂ ; CH ₂ Cl ₂ / MeOH)
/ NH ₄ OH, 19: 1: 0.05) gave the title compound (76 mg, 19%). Light yellow solid. MS (ISP): 390.3 ([M + H] ⁺ ).

Example 8b Cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.690 mm
ol) with cyclopropylmethanesulfonyl chloride (95 mg, 0.83 mmol), prepared according to the procedure detailed in Example 8a. Yield: 113mg
(40%). Yellow solid.

[0123]

[Table 2]

Example 8c 2-Methyl-propane-1-sulfonic acid 6- (2,4-diamino-pyrimidine-
5-ylmethyl) -1-ethyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.690 mm
ol) and 2-methylpropane-1-sulfonyl chloride (218 mg, 1.39 mmol)
) Was prepared according to the procedure detailed in Example 8a. Yield: 6
8 mg (24%). Yellow solid.

[0125]

[Table 3]

Example 8d rac-Butane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-1H-indole-4-ol (Example 6; 196 mg, 0.690 mm
ol) with rac-butane-2-sulfonyl chloride (131 mg, 0.83 mmol), prepared according to the procedure detailed in Example 8a. Yield: 81mg
(29%). Yellow solid.

[0127]

[Table 4]

Example 9 Dimethyl-sulfamic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester. Tetrabutylammonium bromide (61 mg, 0.19 mmol) and 50% aqueous sodium hydroxide solution (7.8 mL) were added to 6- (2,4) in dichloromethane (130 mL).
-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indole-
4-ol (Example 6; 436 mg, 1.54 mmol) was added to the suspension and the mixture was stirred vigorously for 15 minutes. Dimethylsulfamoyl chloride (226 mg, 1.
57 mmol) was added, then after 2 hours more dimethylsulfamoyl chloride (6
0 mg, 0.42 mmol) was added. After 16 hours, the reaction mixture was diluted with dichloromethane (1
The solution was separated into 30 mL) and water (50 mL), the organic layer was washed with brine and dried (MgS
O ₄₎ to the solvent was evaporated. The crude product was purified by preparative HPLC to give the title compound (51 mg, 9%). Light brown solid. MS (ISP): 391.3 ([M + H] ⁺ ).

Example 10a 5- (4-Cyclopropylmethoxy-1-ethyl-3-morpholin-4-ylmethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. Formaldehyde (35% aqueous solution, 41 μL, 0.48 mmol) was added at room temperature to a solution of morpholine (142 mg, 1.60 mmol) in acetic acid (1.6 mL) and water (0.2 mL). After 10 minutes, 5- (4-cyclopropylmethoxy-1-ethyl-1)
H-indol-6-ylmethyl) -pyrimidine-2,4-diamine (Example 7)
a; 134 mg, 0.40 mmol) was added, then after 45 minutes the solution was concentrated.
By adding 1M aqueous sodium hydroxide solution (10 mL) to the viscous residue, the resulting suspension was then stirred at room temperature for 1 hour, the solvent was removed and the gummy precipitate was washed with water and dried. , The title compound (121 mg, 69%) was obtained. Off-white solid. MS (ISP): 350.4 ([M-C ₄ H ₈ NO] ^+), 437.5 ([M + H
] ⁺ )

Example 10b 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-3-morpholin-4-ylmethyl-1H-indole-4-propan-2-sulfonic acid
Ilester. This compound was prepared from propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester (Example 8a; 400 mg, 1.03 mmol), Formaldehyde (35% aqueous solution, 10
Prepared from 6 μL, 1.23 mmol) and morpholine (358 mg, 4.11 mmol) according to the procedure detailed in Example 10a. Yield: 353 mg (70%).
Light yellow solid. MS (ISP): 402.5 ([M-C ₄ H ₈ NO] ^+), 489.4 ([M + H
] ⁺ )

Example 10c Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-3-thiomorpholin-4-ylmethyl-1H-indole-
4-yl ester. This compound was prepared from propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester (Example 8a; 105 mg, 0.27 mmol), Thiomorpholine (114mg, 1.08mm
ol) and formaldehyde (35% aqueous solution, 28 μL, 0.32 mmol),
Prepared according to the procedure detailed in Example 10a. Yield: 108 mg (80%)
. White solid. MS (ISP): 402.5 ([M-C ₄ H ₈ NS] ^+), 505.3 ([M + H
] ⁺ )

Example 10d (cis / trans) -propane-2-sulfonic acid 6- (2,4-diamino-)
Pyrimidin-5-ylmethyl) -3- (2,6-dimethyl-morpholin-4-ylmethyl) -1-ethyl-1H-indol-4-yl ester. This compound was prepared from propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester (Example 8a; 105 mg, 0.27 mmol), Prepared from (cis / trans) -2,6-dimethylmorpholine (128 mg, 1.08 mmol) and formaldehyde (35% aqueous solution, 28 μL, 0.32 mmol) according to the procedure detailed in Example 10a. Yield: 97 mg (69%). Off-white solid. MS (ISP): 402.5 ([M-C ₆ H ₁₀ NO] ^+), 517.3 ([M + H
] ⁺ )

Example 10e Cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-3-morpholin-4-ylmethyl-1H-indol-4-yl ester. This compound is cyclopropyl-methanesulfonic acid 6- (2,4-diamino-
Pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester (Example 8b; 129 mg, 0.32 mmol), morpholine (114 mg, 1.2).
8 mmol) and formaldehyde (35% aqueous solution, 33 μL, 0.38 mmol) according to the procedure detailed in Example 10a. Yield: 138 mg (86
%). Light yellow solid. MS (ISP): 414.3 ([M-C ₄ H ₈ NO] ^+), 517.3 ([M + H
] ⁺ )

Example 11 Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-3-formyl-1H-indol-4-yl ester. Phosphorus oxychloride (133 mg, 0.867 mmol) was added to N, N-dimethylformamide (0.95 mL) at -5 ° C over 20 minutes. Then propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H
-Indol-4-yl ester (Example 8a; 277 mg, 0.710 mmol) was added at + 2 ° C and the reaction mixture was stirred at 40 ° C for 5.5 hours. After evaporation of the solvent and addition of saturated aqueous sodium carbonate solution (15 mL) and ethanol (1 mL), the resulting mixture was stirred at room temperature for 2 hours. Extract with ethyl acetate, wash the organic layer with water and brine, dry (MgSO ₄ ), evaporate the solvent and purify by preparative HPLC to give the title compound (32 mg, 11%). It was White solid. MS (ISP): 418.3 ([M + H] ⁺ ).

Example 12a Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-3-methyl-1H-indol-4-yl ester. Propane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-3-morpholin-4-ylmethyl-1H-indole-4
-Yl ester (Example 10d; 270 mg, 0.55 mmol) in methanol (50
mL) and 1M aqueous hydrochloric acid (0.6 mL) and hydrogenated in the presence of palladium on activated carbon (10%, 170 mg) at room temperature and atmospheric pressure for 16 hours. The catalyst was removed by filtration through filter aid and the filtrate was concentrated. The residue was dissolved in water (10 mL) and the pH was adjusted to ≈9 with 25% aqueous ammonia solution. The precipitate was collected by filtration and purified by preparative HPLC to give the title compound (63 mg, 28
%) Was obtained. Off-white solid. MS (ISP): 404.5 ([M + H] ⁺ ).

Example 12b Cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-3-methyl-1H-indol-4-yl ester. This compound is cyclopropyl-methanesulfonic acid 6- (2,4-diamino-
Pyrimidin-5-ylmethyl) -1-ethyl-3-morpholin-4-ylmethyl-1H-indol-4-yl ester (Example 10e; 250 mg, 0.50 mm
ol) was prepared according to the procedure detailed in Example 12a. Yield: 164mg
(75%). Off-white solid.

[0137]

[Table 5]

Example 13 5- (3-Bromo-4-cyclopropylmethoxy-1-ethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
Prepared from -ethyl-1H-indole-4-ol (Example 6) via steps a) -b) as described below.

A) 3-Bromo-6- (2,4-diamino-pyrimidin-5-ylmethyl) -1
-Ethyl-1H-indole-4-ol. Bromine (192 mg, 1.20 mmol) in N, N-dimethylformamide (4 mL)
Solution of 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1 at room temperature.
A solution of -ethyl-1H-indole-4-ol (283 mg, 1.00 mmol) was added over 45 minutes. After 1 hour, the mixture was poured into ice-cold 0.5% aqueous ammonia solution (200 mL) containing 0.1% sodium metabisulfite and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. Methanol was added to the gummy residue to give a precipitate, which was collected by filtration and dried to give the title compound (90 mg, 25%).
Off-white solid. MS (ISP): 362.1 / 364.1 ([M + H] ⁺ ).

B) 5- (3-Bromo-4-cyclopropylmethoxy-1-ethyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound was prepared from 3-bromo-6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indole-4-ol (77 mg, 0.21 mmol).
) With (bromomethyl) cyclopropane (34 mg, 0.26 mmol) prepared according to the procedure detailed in Example 5a. Yield: 34 mg (38%).
Light brown solid. MS (ISP): 416.4 / 418.4 ([M + H] ⁺ ).

Example 14 (Key Intermediate) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-2-methyl-1H-indol-4-ol. This compound was prepared from (4-benzyloxy-1H-indol-6-yl) -methanol (DE 2508251) via steps a) -i) as described below.

A) rac-4-Benzyloxy-6- (tetrahydro-pyran-2-yloxymethyl) -1H-indole. (4− in dichloromethane (150 mL) and tetrahydrofuran (150 mL)
Benzyloxy-1H-indol-6-yl) -methanol (19.1 g, 7
5.3 mmol), 3,4-dihydro-2H-pyran (19.0 g, 226 mmol),
A solution of toluene and pyridinium toluene-4-sulfonate (1.89 g, 7.53 mmol) was stirred at room temperature for 1 hour. Then the solution was diluted with ethyl acetate, washed with water and brine, dried (MgSO ₄₎ and the solvent was evaporated. Flash chromatography (SiO _2; n-hexane / ethyl acetate _{/ NH 4 OH, 75: 25} : 0.1
To give the title compound (21.4 g, 84%). White solid. MS (EI): 337.2 (M ⁺ ).

B) rac-1-benzenesulfonyl-4-benzyloxy-6- (tetrahydro-pyran-2-yloxymethyl) -1H-indole. rac-4-benzyloxy-6- (tetrahydro-pyran-2-yloxymethyl) -1H-indole (21.4 g, 63.3 mmol) and tetrabutylammonium hydrogen sulfate (32.2 g, 95.0 mmol) in toluene. Heat in (150 mL) until dissolved. After addition of 2M aqueous sodium hydroxide solution (40 mL), benzenesulfonyl chloride (16.8 g, 95.0 mmol) in toluene (90 mL).
Solution was added at room temperature over 5 minutes. After 45 minutes, the two phase mixture was poured into ice and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO _4),
The solvent was distilled off. Flash chromatography (SiO _2; n-hexane / ethyl acetate _{/ NH 4 OH, 85: 15} : 0.1) by the title compound (28.4 g,
94%). Colorless rubber. MS (EI): 477.1 (M ⁺ ).

C) rac-1-benzenesulfonyl-4-benzyloxy-2-methyl-6-
(Tetrahydro-pyran-2-yloxymethyl) -1H-indole. Rac-1-benzenesulfonyl-4-in tetrahydrofuran (150 mL)
Benzyloxy-6- (tetrahydro-pyran-2-yloxymethyl) -1H
-Cool the solution of indole (28.4g, 59.5mmol) to -30 ° C and
rt-Butyllithium (1.5 M solution in n-pentane, 79.3 mL, 119 mm
ol). Wait for the solution to warm to room temperature, then cool to -30 ° C,
Iodomethane (21.1 g, 149 mmol) in tetrahydrofuran (100 mL)
Was treated with the above solution. The resulting solution was allowed to reach room temperature, then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. Flash chromatography (Si
O ₂ ; n-hexane / ethyl acetate / NH ₄ OH, 80: 20: 0.1) followed by recrystallization in methanol to give the title compound (13.4 g, 46%). White solid. MS (EI): 491.1 (M ⁺ ).

D) (1-Benzenesulfonyl-4-benzyloxy-2-methyl-1H-indol-6-yl) -methanol. Rac-1-benzenesulfonyl-4-benzyloxy-2-methyl-6- (tetrahydro-pyran-2-yloxymethyl)-in ethanol (500 mL)
A mixture of 1H-indole (10.1 g, 20.6 mmol) and pyridinium toluene-4-sulfonate (518 mg, 2.06 mmol) was stirred at 60 ° C. for 3 hours.
Evaporation of the solvent followed by flash chromatography (SiO ₂ ; n-hexane / ethyl acetate / NH ₄ OH, 70: 30: 0.1) gave the title compound (7.55 g,
90%). White solid. MS (ISP): 408.3 ([M + H] ⁺ ).

E) 1-Benzenesulfonyl-4-benzyloxy-2-methyl-1H-indole-6-carbaldehyde. This compound comprises (1-benzenesulfonyl-4-benzyloxy-2-methyl-1H-indol-6-yl) -methanol (7.50 g, 18.4 mmol) and manganese dioxide (17.8 g, 184 mmol). Depending on the reaction, Example 1, step c
Prepared according to the procedure detailed in. Yield: 7.25 g (97%). White solid. MS (EI): 405.0 (M ⁺ ).

F) 4-Benzyloxy-2-methyl-1H-indole-6-carbaldehyde. 1-Benzenesulfonyl-4-benzyloxy-2-methyl-1H-indole-6-carbaldehyde (7.45 g, 18.3 mmol) was added to methanol (550 mL).
) And tetrahydrofuran (150 mL) until dissolved. After addition of 2M aqueous potassium hydroxide solution (186 mL), the resulting suspension was stirred at 70 ° C. for 1 hour. The solvent was distilled off to obtain a residue, which was partitioned between ether and water. The organic layer was washed with brine, dried (MgSO ₄ ) and evaporated to give the title compound (4.87 g, 100%). Light yellow solid. MS (EI): 265.1 (M ⁺ ).

G) 4-Benzyloxy-1-ethyl-2-methyl-1H-indole-6-carbaldehyde. This compound is 4-benzyloxy-2-methyl-1H-indole-6-carbaldehyde (4.87 g, 18.4 mmol) and bromoethane (6.00 g, 55
． 1 mmol) was prepared according to the procedure detailed in Example 6, step a. Yield: 4.45 g (83%). Yellow solid. MS (ISP): 294.3 ([M + H] ⁺ ).

H) 5- (4-benzyloxy-1-ethyl-2-methyl-1H-indole-
6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 4-benzyloxy-1-ethyl-2-methyl-1H-indole-6-carbaldehyde (2.50 g, 8.52 mmol), 3-anilinopropionitrile (1.18 g, 8.10 mmol). , And guanidine hydrochloride (2.69 g,
28.1 mmol) according to the procedure detailed in Example 4, step f.
Yield: 1.66 g (50%). Yellow solid. MS (ISP): 388.2 ([M + H] ⁺ ).

I) 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-2
-Methyl-1H-indole-4-ol. 5- (4-benzyloxy-1-ethyl-2-methyl-1H-indol-6-ylmethyl)-in methanol (75 mL) and tetrahydrofuran (30 mL).
A mixture of pyrimidine-2,4-diamine (1.55 g, 4.00 mmol) and palladium on activated carbon (10%, 77.5 mg) was hydrogenated at atmospheric pressure and room temperature for 1 hour. The suspension was passed through a filter aid, which was thoroughly washed with hot N, N-dimethylformamide. Evaporation of the solvent from the filtrate and flash chromatography (SiO ₂ ; CH ₂ Cl ₂ : MeOH: NH ₄ OH, 90: 10: 0.25) gave the title compound (1.08 g, 91%). Orange solid. MS (ISP): 298.3 ([M + H] ⁺ ).

Example 15a 5- (4-Ethoxy-1-ethyl-2-methyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-2-methyl-1H-indole-4-ol (Example 14; 83 mg,
Prepared by reaction of 0.28 mmol) with bromoethane (32 mg, 0.29 mmol) according to the procedure detailed in Example 5a. Yield: 89 mg (98%). Brown solid. MS (ISP): 326.4 ([M + H] ⁺ ).

Example 15b 5- (4-Cyclopropylmethoxy-1-ethyl-2-methyl-1H-indol-6-ylmethyl) -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-2-methyl-1H-indole-4-ol (Example 14; 800 mg
, 1.69 mmol) and (bromomethyl) cyclopropane (381 mg, 2.82 mm
was prepared according to the procedure detailed in Example 5a. Yield: 67 mg (7
2%). Light brown solid. MS (ISP): 352.4 ([M + H] ⁺ ).

Example 15c rac-Butane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-2-methyl-1H-indol-4-yl ester. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-2-methyl-1H-indole-4-ol (Example 14; 250 mg
, 0.841 mmol) and rac-butane-2-sulfonyl chloride (184 mg, 1
． 18 mmol) and prepared according to the procedure detailed in Example 8a. Yield: 70 mg (20%). Orange foam.

[0154]

[Table 6]

Example 16 (Key Intermediate) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-3- (
3-Methoxy-phenyl) -1H-indole-4-ol. This compound was prepared from 4-benzyloxy-1H-indole-6-carboxylic acid methyl ester (DE 2508251) via steps a) -g) as described below.

A) 4-Benzyloxy-1-ethyl-1H-indole-6-carboxylic acid methyl ester. This compound is 4-benzyloxy-1H-indole-6-carboxylic acid methyl ester (43.9 g, 156 mmol) and bromoethane (19.3 g, 172 mm).
ol) was prepared according to the procedure detailed in Example 6, step a.
Yield: 48.2 g (100%). Brown solid. MS (EI): 309.2 (M ⁺ ).

B) 4-Benzyloxy-3-bromo-1-ethyl-1H-indole-6-carboxylic acid methyl ester. Bromine (1.55 g, 9.70 mmol) in N, N-dimethylformamide (5 mL)
4) in N, N-dimethylformamide (85 mL) at room temperature over 3 minutes.
-Benzyloxy-1-ethyl-1H-indole-6-carboxylic acid methyl ester (3.00 g, 9.70 mmol) was added to the solution. After 16 hours, the reaction mixture was treated with 0.5% aqueous ammonia solution containing 600% sodium metabisulfite (600 mL).
) And extracted with ethyl acetate. The organic layer was washed with brine and dried (M
gSO ₄ ) and the solvent was distilled off. Column chromatography (SiO ₂ ; n-hexane / ethyl acetate, 5: 1) gave a crude product which was washed with n-hexane to give the title compound (1.95 g, 52%). It was White solid.
MS (EI): 387.0 / 389.0 (M ⁺ ).

C) 4-Benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H
-Indole-6-carboxylic acid methyl ester. 4-Benzyloxy-3-bromo-1-ethyl-1H-indole-6-carboxylic acid methyl ester (1.88 g, 4.85 mmol) and 3-methoxybenzeneboronic acid in ethanol (1.14 g, 7.28 mmol). ) Solution at room temperature for 1,2
-Add a suspension of tetrakis (triphenylphosphine) palladium (280 mg, 0.242 mmol) in dimethoxyethane (3 mL). After 10 minutes, 2M aqueous sodium carbonate solution (20.6 mL) was added and the mixture was stirred at 90 ° C. for 1 hour. Next, the organic solvent was distilled off, and the resulting mixture was partitioned into water and dichloromethane. The organic layer was washed with brine, dried (MgSO ₄₎ and the solvent was evaporated. By column chromatography (SiO ₂ ; hexane / ethyl acetate, 5: 1), the title compound (1
． 37 g, 68%) was obtained. Yellow rubber. MS (ISP): 416.3 ([M + H] ⁺ ).

D) [4-Benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1
H-indol-6-yl] -methanol. This compound was prepared from 4-benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H-indole-6-carboxylic acid methyl ester (1.32 g, 3.
17 mmol) with diisobutylaluminium hydride (1M solution in tetrahydrofuran, 13 mL, 13 mmol) prepared according to the procedure detailed in Example 1, step b. Yield: 1.17 g (95%). MS (EI): 387.1 (M ⁺ ).

E) 4-Benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H
-Indole-6-Carbaldehid. This compound was prepared as [4-benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H-indol-6-yl] -methanol (1.10 g, 2.84).
mmol) with manganese dioxide (1.23 g, 14.2 mmol), prepared according to the procedure detailed in Example 1, step c. Yield: 1.09g (100%
). Brown oil. MS (EI): 385.1 (M ⁺ ).

F) 5- [4-benzyloxy-1-ethyl-3- (3-methoxy-phenyl)
-1H-Indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound was prepared from 4-benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H-indole-6-carbaldehyde (940 mg, 2.44 mmol),
Prepared from 3-anilinopropionitrile (392 mg, 2.68 mmol) and guanidine hydrochloride (859 mg, 8.99 mmol) according to the procedure detailed in Example 1, step e. Yield: 711 mg (61%). Light brown solid. MS (ISP): 480.4 ([M + H] ⁺ ).

G) 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-3
-(3-Methoxy-phenyl) -1H-indole-4-ol. This compound was prepared from 5- [4-benzyloxy-1-ethyl-3- (3-methoxy-phenyl) -1H-indol-6-ylmethyl] -pyrimidine-2,4-diamine (650 mg, 1.36 mmol). Prepared by hydrogenation according to the procedure detailed in Example 14, Step i. Yield: 505 mg (93%). Off-white solid. MS (ISP): 390.3 ([M + H] ⁺ ).

Example 17a 5- [4-Ethoxy-1-ethyl-3- (3-methoxy-phenyl) -1H-indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-3- (3-methoxy-phenyl) -1H-indole-4-ol (
Example 16; 150 mg, 0.39 mmol) and iodoethane (66 mg, 0.42 mmol)
) Was prepared according to the procedure detailed in Example 5a. Yield: 4
2 mg (26%). Brown solid. MS (ISP): 418.3 ([M + H] ⁺ ).

Example 17b 5- [1-Ethyl-4-methoxy-3- (3-methoxy-phenyl) -1H-indol-6-ylmethyl] -pyrimidine-2,4-diamine. This compound is 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1.
-Ethyl-3- (3-methoxy-phenyl) -1H-indole-4-ol (
Example 16; 100 mg, 0.26 mmol) and iodomethane (44 mg, 0.31 mmol)
) Was prepared according to the procedure detailed in Example 5a. Yield: 3
5 mg (34%). Brown solid. MS (ISP): 404.5 ([M + H] ⁺ ).

[0165] Example A tablet: 400 mg of sulfamethoxazole Compounds of formula (I), for example cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1- Ethyl-1H-indol-4-yl ester 80 mg PRIMOJEL (starch derivative) 6mg Povidone K30 (Polyvinylpyrrolidone) 8mg Magnesium stearate 6mg                                               Total weight 500mg

[0166] Example B tablet: Compounds of formula (I), for example 2-methyl-propane-1-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1- Ethyl-1H-indol-4-yl ester 100 mg Corn starch 15mg Talc 3 mg Magnesium stearate 2mg                                               Total weight 120mg

[0167] Example C Injection solution: A compound of formula (I), for example rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1- Ethyl-1H-indol-4-yl ester 5 mg Glycofurol 75 0.2 ml Add sterile double distilled water to 1.0 ml

[0168] Example D Injection solution: A compound of formula (I), for example rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1- Ethyl-1H-indol-4-yl ester 5 mg Propylene glycol 0.5 ml Add sterile double distilled water to 1.0 ml

[Procedure amendment]

[Submission date] November 7, 2002 (2002.1.7)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

[Chemical 1] [In the formula, R ¹ represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, Heterocyclylalkyl or phenylalkyl; R ² is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl; R ³ is hydrogen, alkyl; and R ⁴ is alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulf Moil, heterocyclylalkyl or phenylalkyl]
And an pharmaceutically acceptable acid addition salt of these compounds.

[Chemical 2] [Wherein R ^{1 to} R ⁴ have the same meanings as in claim 1 and X represents a leaving group].

[Chemical 3] [Wherein R ³ has the same meaning as in claim 1 and R ^1A , R ^2A and R ^4A have the same meanings as R ¹ , R ² and R ⁴ defined in claim 1, but at least One is hydrogen].

[Chemical 4] [Wherein R ^{1 to} R ⁴ have the same meanings as in claim 1 and X represents a leaving group], or a compound represented by the formula (III) ):

[Chemical 5] [Wherein R ³ has the same meaning as in claim 1, and R ^1A , R ^2A and R ^4A have the same meanings as R ¹ , R ² and R ⁴ defined in claim 1, but at least One is
Hydrogen atom] is introduced into the compound represented by the formula: at least one of the groups R ¹ , R ² and R ⁴ , or iii) a pharmaceutically acceptable salt of the compound of formula (I) according to claim 1. A method characterized by converting to.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07D 403/14 C07D 403/14 413/14 413/14 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ , BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CO, C , CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL , TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZWF F term (reference) 4C063 AA01 AA03 BB03 CC29 CC54 DD06 EE01 4C086 AA01 AA02 AA03 AA04 BC42 BC73 BC88 GA07 GA09 MA01 MA04 NA14 ZB35

Claims (20)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ¹ represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulfamoyl, Heterocyclylalkyl or phenylalkyl; R ² is hydrogen, halogen, alkyl, alkanoyl, phenyl, phenylalkyl or heterocyclylalkyl; R ³ is hydrogen, alkyl; and R ⁴ is alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkylalkyl, alkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, dialkylsulfamoyl, N-cycloalkyl-N-alkylsulf Moil, heterocyclylalkyl or phenylalkyl]
And an pharmaceutically acceptable acid addition salt of these compounds. 2. The compound according to claim 1, wherein R ¹ is alkylsulfonyl, cycloalkylsulfonyl or cycloalkylalkylsulfonyl. 3. R ¹ is isopropylsulfonyl, isobutylsulfonyl,
The compound according to claim 2, which is sec-butylsulfonyl, cyclopropylsulfonyl or cyclopropylmethylsulfonyl. 4. The compound according to any one of claims 1 to 3, wherein R ² is hydrogen or alkyl. 5. The compound according to claim 4, wherein R ² is methyl. 6. The method according to claim 1, wherein R ³ is hydrogen or methyl.
The compound according to the item. 7. The compound according to any one of claims 1 to 6, wherein R ⁴ is alkyl. 8. The compound according to claim 7, wherein R ⁴ is ethyl. 9. Cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester; 2-methyl-propane-1-sulfonic acid 6- (2,4-Diamino-pyrimidin-5-ylmethyl) -1-ethyl-1H-indol-4-yl ester; rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidine-5-
Ilmethyl) -1-ethyl-1H-indol-4-yl ester; cyclopropyl-methanesulfonic acid 6- (2,4-diamino-pyrimidine-5
-Ylmethyl) -1-ethyl-3-methyl-1H-indol-4-yl ester; and rac-butane-2-sulfonic acid 6- (2,4-diamino-pyrimidine-5-
A compound according to claim 1 selected from ylmethyl) -1-ethyl-2-methyl-1H-indol-4-yl ester. 10. General formula (II): [Wherein R ^{1 to} R ⁴ have the same meanings as in claim 1 and X represents a leaving group]. 11. General formula (III): [Wherein R ³ has the same meaning as in claim 1 and R ^1A , R ^2A and R ^4A have the same meanings as R ¹ , R ² and R ⁴ defined in claim 1, but at least One is hydrogen]. 12. A medicament comprising a compound according to any one of claims 1 to 9 and a therapeutically inert carrier. 13. The medicine according to claim 12, further comprising sulfonamide. 14. The ratio of the present compound to the sulfonamide is from 1:40 to 1:
14. Medicament according to claim 13, which is between 1 part by weight, preferably between 1:10 and 1: 2 parts by weight. 15. A method for producing the compound according to any one of claims 1 to 9, wherein i) the general formula (II): [Wherein R ^{1 to} R ⁴ have the same meanings as in claim 1 and X represents a leaving group], or a compound represented by the formula (III) ): [Chemical 5] [Wherein R ³ has the same meaning as in claim 1, and R ^1A , R ^2A and R ^4A have the same meanings as R ¹ , R ² and R ⁴ defined in claim 1, but at least One is
Hydrogen radical] is introduced into the compound represented by the formula: at least one of the groups R ¹ , R ² and R ⁴ , or iii) the compound of formula (I) is converted into a pharmaceutically acceptable salt. How to characterize. 16. A compound according to any one of claims 1 to 9 prepared by the method of claim 15 or by its obvious chemical equivalent method. 17. A compound according to any one of claims 1 to 9 for use as a medicament. 18. A method according to claim 1 in the manufacture of a medicament which is active as an antibiotic.
10. Use of a compound according to any one of 1-9. 19. A method for the prophylaxis and / or therapeutic treatment of infectious diseases, comprising:
A method comprising administering to a human an effective amount of a compound according to any one of claims 1-9. 20. The invention described herein.